Effectiveness and safety of afatinib, gefitinib, and erlotinib for treatment-naïve elderly patients with epidermal growth factor receptor-mutated advanced non-small-cell lung cancer: a multi-institute retrospective study.

BACKGROUND: In real-world practice, most patients with lung cancer are diagnosed when they are aged ≥65 years. However, clinical trials tend to lack data for the elderly population. Therefore, we aimed to describe the effectiveness and safety of afatinib, gefitinib, and erlotinib for elderly patients with epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC). METHODS: Treatment-naïve patients with EGFR-mutated advanced NSCLC were enrolled at many hospitals in Taiwan. Patient characteristics and the effectiveness and safety of afatinib, gefitinib, and erlotinib were compared. RESULTS: This study enrolled 1,343 treatment-naïve patients with EGFR-mutated advanced NSCLC, of whom 554 were aged <65 years, 383 were aged 65-74 years, 323 were aged 75-84 years, and 83 were aged ≥85 years. For elderly patients, afatinib was more effective, with a median progression-free survival (PFS) of 14.7 months and overall survival (OS) of 22.2 months, than gefitinib (9.9 months and 17.7 months, respectively) and erlotinib (10.8 months and 18.5 months, respectively; PFS: p = 0.003; OS: p = 0.026). However, grade ≥3 adverse events, including skin toxicities, paronychia, mucositis, and diarrhea, were more frequently experienced by patients receiving afatinib than those receiving gefitinib or erlotinib. CONCLUSIONS: This large retrospective study provides real-world evidence of the effectiveness and safety of EGFR-TKIs for elderly patients with EGFR-mutated advanced NSCLC, a population that is often underrepresented in clinical trials and real-world evidence. Afatinib was more effective as a first-line treatment than gefitinib or erlotinib for elderly patients with EGFR-mutated advanced NSCLC.

Generation and validation of a predictive model for estimating survival among patients with EGFR-mutant non-small cell lung cancer.

Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have become the standard therapy for patients with EGFR-mutant non-small cell lung cancer (NSCLC), treatment outcomes vary significantly. Previous studies have indicated that concurrent mutations may compromise the effectiveness of first-line EGFR-TKIs. However, given the high cost of next-generation sequencing, this information is often inaccessible in routine clinical practice. A prediction model based on pre-treatment clinical characteristics may thus offer a more practical solution. This study established a nomogram based on pretreatment clinical characteristics to stratify patients according to optimal treatment strategies. We retrospectively reviewed 761 patients with EGFR-mutant NSCLC who received first- or second-generation EGFR-TKIs at a tertiary referral center between 2010 and 2019. The pretreatment clinical characteristics and progression-free survival data were collected. Using COX proportional hazard regression analysis, we constructed a nomogram based on seven clinically significant prognostic factors: sex, Eastern Cooperative Oncology Group performance status, histology subtype, mutation subtype, stage, and metastasis to the liver and brain. Our nomogram could stratify patients into three groups with different risks for disease progression and was validated in a patient cohort from other hospitals. This risk stratification can provide additional information for determining the optimal first-line treatment strategy for patients with EGFR-mutant NSCLC.

Comprehensive assessment of pretreatment sarcopenia impacts on patients with EGFR-mutated NSCLC treated with afatinib.

BACKGROUND: This study aimed to comprehensively evaluate the efficacy and toxicity of afatinib in patients with sarcopenia, an important prognostic factor for treatment efficacy and toxicity in patients with cancer. METHODS: The clinical features of patients with advanced NSCLC treated with frontline afatinib between 2014 and 2018 at a medical center in Taiwan were retrospectively reviewed. Sarcopenia was evaluated based on the total cross-sectional area of skeletal muscles assessed by computed tomography (CT) imaging at the L3 level. Baseline characteristics, response rates, survival rates, and adverse events (AEs) were compared between sarcopenic and nonsarcopenic patients. RESULTS: A total of 176 patients evaluated for sarcopenia by CT and treated with afatinib were enrolled in the current study. Sarcopenia was significantly associated with good performance status, low body mass index (BMI), low body surface area (BSA), and low total mass area (TMA). Sarcopenia did not influence the response rate (69.2% vs. 72.0%, p = 0.299), progression-free survival (median 15.9 vs. 14.9 months, p = 0.791), or overall survival (median 26.5 vs. 27.2 months, p = 0.441). However, BSA ≤ 1.7 and the 40 mg afatinib dose were associated with dose reduction. TMA was the only independent factor for afatinib discontinuation due to AEs. CONCLUSION: Sarcopenia was not associated with treatment efficacy or toxicity among patients with NSCLC harboring common mutations treated with afatinib, indicating sarcopenic patients should not be excluded from afatinib treatment. Other factors, such as BSA and TMA, were associated with dose reduction and afatinib discontinuation, respectively, which may require additional evaluations in future studies.

The survival after discontinuation of EGFR-TKIs due to intolerable adverse events in patients with EGFR-mutated non-small cell lung cancer.

BACKGROUND: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are standard treatments for advanced non-small cell lung cancer (NSCLC) patients harboring the EGFR mutation. Patients experiencing intolerable adverse events (AEs) would discontinue EGFR-TKIs. This study aimed to evaluate the impact of intolerable AEs and subsequent treatment on the survival of patients who discontinued EGFR-TKIs. PATIENTS: The data of advanced NSCLC patients treated with EGFR-TKIs as frontline treatment at Chang Gung Memorial Hospitals from June 2014 to March 2018 were retrospectively reviewed. RESULTS: A total of 2190 patients were enrolled and treated with frontline EGFR-TKIs. In August 2021, 114 (5.2%) patients experienced intolerable AEs requiring discontinuation of EGFR-TKIs. The time median of EGFR-TKIs discontinuation was 2.56 months. Age >65 years, females, body weight, and body surface area were associated with the occurrence of intolerable AEs for patients treated with afatinib. Patients experiencing skin/paronychia/mucositis and abnormal liver function test had favorable survivals results. Patients who received subsequent EGFR-TKIs treatment, experienced better progression-free survival (PFS), total PFS (from frontline line EGFR-TKIs), and overall survival (OS) compared to patients receiving chemotherapy or no treatment. Patients undergoing subsequent EGFR-TKIs had better total PFS (median, 14.9 vs. 11.3 months, p = 0.013) and OS (median, 31.3 vs. 20.1 months, p = 0.001) than patients who did not discontinue because of AEs. Favorable OS was validated by propensity score matching. CONCLUSION: Patients experiencing intolerable AEs during EGFR-TKI treatment should consider switching to an alternative EGFR-TKI, which increase the survival results as compared to those patients who did not experience intolerable AEs.

Epidermal growth factor receptor tyrosine kinase inhibitors for non-small cell lung cancer harboring uncommon EGFR mutations: Real-world data from Taiwan.

BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the standard treatment for patients with non-small cell lung cancer (NSCLC) harboring EGFR mutations. This study aimed to evaluate the efficacy of EGFR-TKIs and prognostic factors for patients with NSCLC harboring uncommon EGFR mutations, which account for 10% of EGFR mutations. METHODS: A total of 230 treatment-naive patients with NSCLC harboring uncommon EGFR mutations treated with first-line EGFR-TKIs between 2011 and 2018 at four hospitals (belonging to four institutions, Linkou, Kaohsiung, Keelung, and Chiayi, of the Chang Gung Memorial Hospital) in Taiwan were retrospectively reviewed. Their clinicopathological characteristics, adverse events (AEs), objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were collected. Univariate and multivariate analyses were performed to identify potential prognostic factors for PFS. RESULTS: Overall, patients who received afatinib (n = 62) had better PFS (median: 6.4 vs. 5.9 months, p = 0.022) and OS (median: 13.4 vs. 13.0 months, p = 0.008) than those who received gefitinib/erlotinib (n = 124), although no significant differences were observed for ORR (46.8% vs. 35.5%, p = 0.137) or DCR (59.7% vs. 58.9%, p = 0.916). Patients who received afatinib showed significantly higher ORR (58.3% vs. 31.3%, p = 0.027) but not DCR compared with gefitinib/erlotinib for major uncommon mutations. Afatinib trended toward better PFS and OS for major uncommon mutations and compound mutations. No EGFR-TKIs were effective for most NSCLC patients with exon 20 insertions. Performance status, metastasis of the liver and pleura, and dose reduction were independent prognostic factors for PFS. CONCLUSION: Afatinib demonstrated better survival outcomes than gefitinib/erlotinib for NSCLC patients harboring major EGFR uncommon mutations and compound mutations. Performance status and metastatic sites may be useful for predicting PFS for major uncommon mutations and compound mutations.

Long-term use and risk of major adverse cardiac events: Comparing enzalutamide and abiraterone in chemotherapy-naïve patients with metastatic castration-resistant prostate cancer.

This is a retrospective cohort study by analyzing a multi-institutional electronic medical records database in Taiwan to compare long-term effectiveness and risk of major adverse cardiac events (MACE) in chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) patients treated with enzalutamide (ENZ) or abiraterone (AA). Patients aged 20 years and older and newly receiving androgen receptor targeted therapies ENZ or AA from September 2016 to December 2019 were included. We followed patients from initiation of therapies to the occurrence of outcomes (prostate-specific antigen (PSA) response rate, PSA progression free survival (PFS), overall survival (OS), and MACE), death, the last clinical visit, or December 31, 2020. We performed multivariable Cox proportional hazard models to compare ENZ and AA groups for the measured outcomes. A total of 363 patients treated with either ENZ (n = 157) or AA (n = 206) were identified. The analysis found a significantly higher proportion of patients with a PSA response rate higher than 50% among those receiving ENZ than among those receiving AA (ENZ vs AA: 75.80% vs 63.59%, P = .01). However, there was no significant difference in PSA PFS (adjusted hazard ratio: 0.86; 95% CI 0.63-1.17) and OS (0.68: 0.41-1.14) between the use of ENZ and AA in chemotherapy-naïve mCRPC patients. Regarding the cardiovascular (CV) safety outcome, there was a significantly lower risk of MACE in patients receiving ENZ, compared to patients receiving AA (0.20: 0.07-0.55). The findings suggest that enzalutamide may be more efficacious for PSA response and suitable for chemotherapy-naïve mCRPC patients with high CV risk profile.

The impact of BRAF targeting agents in advanced anaplastic thyroid cancer: a multi-institutional retrospective study in Taiwan.

Anaplastic thyroid cancer (ATC) is a rare but lethal thyroid cancer. Dabrafenib and trametinib has been the standard treatment for the patients with BRAF mutation based on phase II study. This study aimed to exam the impact of dabrafenib and trametinib in ATC patients. ATC patients treated in three institutes in Taiwan were retrospectively reviewed. The clinical features, BRAF status, and survivals were collected. Multivariate analysis was performed to determine the independent prognostic factors. A total of 44 ATC patients were enrolled in current study. Twelve (50%) out of 24 detected patients had BRAF V600E mutation and eleven received dabrafenib and trametinib treatment. Patients treated with dabrafenib and trametinib had longer overall survival (OS) than the patients without treatment with dabrafenib and trametinib (median OS: 10.4 months vs. 3.3 months, P=0.05). The objective response rate was 81.8% and progress-free survival was 7.4 months. Multivariate analysis identified prior surgery, treatment with dabrafenib and trametinib and metastasis to lung, brain, and bone were significant prognostic factors for OS. The benefit of prior surgery was significant in patients receiving dabrafenib and trametinib (P=0.017) rather than those without dabrafenib and trametinib (P=0.067). The current study provides the real-world evidence that targeted therapy with dabrafenib and trametinib was effective and significantly improved the OS for ATC patients. The role of prior surgery became important in the era of targeted therapy. Future studies should focus on resistance mechanisms and combination with immunotherapy for ATC patients.

Adjuvant Chemoradiotherapy Associated with Improved Overall Survival in Resected Esophageal Squamous Cell Carcinoma after Neoadjuvant Chemoradiotherapy in Intensity-Modulated Radiotherapy Era.

BACKGROUND: The prognosis of patients with resected esophageal squamous cell carcinoma after neoadjuvant chemoradiotherapy is particularly poor in those who were staged as ypT3/T4 and/or ypN+. This study investigated whether adjuvant chemoradiotherapy was associated with improved clinical outcomes in these patients. METHODS: we identified patients with esophageal squamous cell carcinoma who were staged as ypT3/T4 and/or ypN+ after being treated with neoadjuvant chemoradiotherapy followed by esophagectomy between the years 2013 and 2019. Patients were divided into two groups based on whether they received adjuvant chemoradiotherapy. The Kaplan-Meier method and Cox regression modeling were performed for survival analyses and multivariable analysis, respectively. RESULTS: 76 eligible patients were included in the analyses. The median follow-up for the study cohort was 43.4 months. On Kaplan-Meier analyses of the overall population, adjuvant chemoradiotherapy was associated with significantly improved median overall survival (31.7 months vs. 16.3 months, p = 0.036). On Kaplan-Meier analyses of the 35 matched pairs generated by propensity score matching, adjuvant chemoradiotherapy was associated with significantly longer median overall survival (31.7 months vs. 14.3 months; p = 0.004) and median recurrence-free survival (18.9 months vs. 11.7 months; p = 0.020). In multivariable analysis, adjuvant chemoradiotherapy was independently associated with a 60% reduction in mortality (p = 0.003) and a 48% reduction in risk of recurrence (p = 0.035) after adjusting for putative confounders. In addition, microscopic positive resection margin and Mandard tumor regression grade 3-4 were independently associated with increased mortality and risk of recurrence. While a greater number of lymph nodes dissected was independently associated with significantly improved overall survival, the number of positive lymph nodes was independently associated with significantly worse overall survival and a trend (p = 0.058) towards worse recurrence-free survival. CONCLUSIONS: This study demonstrated that adjuvant CRT was independently associated with a significantly improved survival and lower risk of recurrence than observation in esophageal squamous cell carcinoma patients staged as ypT3 and/or ypN+ after receiving neoadjuvant chemoradiotherapy and radical surgery. The results of this study have implications for the design of future clinical trials and may improve treatment outcomes of patients in this setting who cannot afford or are without access to adjuvant nivolumab.

Impact of T790M Mutation Status on Later-Line Osimertinib Treatment in Non-Small Cell Lung Cancer Patients.

Background: Osimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) designed to overcome acquired T790M resistance mutations in non-small cell lung cancer (NSCLC). However, the efficacy of osimertinib in patients without acquired T790M mutations has not been well studied. This study aimed to evaluate the efficacy of osimertinib in patients treated with first- and second-generation EGFR-TKIs followed by later-line osimertinib treatment. Patients: The clinical data and survival outcomes of 172 patients with advanced NSCLC treated with osimertinib following frontline EGFR-TKIs at Chang Gung Memorial Hospital from 2014 to 2018 were retrospectively reviewed. T790M mutations were detected using tissue sequencing and/or liquid biopsy. Results: A total of 172 EGFR-mutated NSCLC patients treated with frontline EGFR-TKI therapy followed by later-line osimertinib were enrolled in the current study and divided into three groups based on the T790M status (positive, negative, or unknown T790M). Patients with NSCLC harboring acquired T790M mutation treated with osimertinib had the best objective response rate (ORR) (52.6%, 25.0%, and 32.0%, p = 0.044), disease control rate (DCR) (79.3%, 41.7%, and 68.0%, p = 0.011), and progression-free survival (PFS, median PFS, 12.6, 3.1, 10.4 months, p = 0.001) among the three groups (positive, negative, and unknown T790M, respectively). However, a marked difference was found between positive and negative T790M mutations but not between positive and unknown T790M mutations. Univariate analysis was performed to identify potential prognostic factors for PFS in 172 patients treated with osimertinib. Lung metastasis (p < 0.001), brain metastasis (p < 0.009), number of metastatic sites (p < 0.001), PFS with frontline EGFR-TKIs (p = 0.03), and T790M status (p = 0.006) were identified as prognostic factors for PFS with osimertinib. Multivariate analysis showed that lung metastasis (p < 0.001) and PFS with frontline EGFR-TKIs and T790M status were independent prognostic factors. Conclusion: This study confirmed the greater efficacy of later-line osimertinib for NSCLC with acquired T790M mutation than for NSCLC without acquired T790M mutation. Detection of the T790M mutation after frontline treatment (first- and second-generation EGFR-TKI) is crucial for prolonging the survival of NSCLC patients harboring EGFR mutation. Osimertinib may be considered an option for NSCLC with unknown T790M mutations, as a certain subpopulation may benefit from osimertinib.

Sequential treatment in advanced non-small cell lung cancer harboring EGFR mutations.

BACKGROUND: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are standard treatments for advanced EGFR-mutated non-small cell lung cancer (NSCLC) patients. Osimertinib is an effective therapy for NSCLC patients with acquired resistance due to T790M mutation after first- and second-generation EGFR-TKI treatment. This study aimed to analyze the clinical outcomes of sequential therapy following first-line EGFR-TKIs and the predictive factors of an acquired T790M mutation. METHODS: Between January 2014 and December 2018, data from 2190 advanced NSCLC patients with common EGFR mutations (exon 19 deletion and L858R) receiving first- and second-generation EGFR-TKIs in Linkou, Kaohsiung, Chiayi and Keelung Chang Gung Memorial Hospitals were retrospectively retrieved and analyzed. RESULTS: Until August 2021, among 1943 patients who experienced progressive disease, 526 underwent T790M mutation tests, and their T790M-positive rate was 53.6%. Exon 19 deletion mutation and progression-free survival (PFS) of >12 months were positively associated with secondary T790M mutation. Different first-line first- and second-generation EGFR-TKI therapies did not affect the appearance of acquired T790M mutations. The median overall survival (OS) was 58.3 [95% confidence interval (CI): 49.0-67.5] months among the patients with T790M mutation who received second-line osimertinib therapy compared with 31.0 (95% CI: 27.5-34.5) months among the patients without T790M mutation who received chemotherapy alone. The multivariate analysis showed that a poor performance status (score: >2), nonadenocarcinoma histology, stage IV cancer, liver metastasis, brain metastasis, PFS while on first-line EGFR-TKIs, and subsequent chemotherapy without third-generation EGFR-TKIs were significant independent unfavorable prognostic factors for OS. CONCLUSION: This study demonstrated the efficacy of first-line EGFR-TKIs and sequential osimertinib therapy. The results of our study suggest that T790M mutation tests are important for the use of subsequent osimertinib, which yielded favorable survival outcomes.

Systemic Therapy for Gastrointestinal Stromal Tumor: Current Standards and Emerging Challenges.

OPINION STATEMENT: Gastrointestinal stromal tumor (GIST), though rare, is the most common mesenchymal tumors of the gastrointestinal tract. KIT or PDGFRα mutation plays as an oncogenic driver in the majority of GISTs. Surgical resection is the only curative treatment for localized disease. The discovery of imatinib with promising anti-tumor effect and successive tyrosine kinase inhibitors (TKI), including second-line sunitinib and third-line regorafenib, revolutionized the management of advanced and metastatic GIST over the past two decades. Recently, ripretinib and avapritinib were approved for the fourth line setting and for PDGFRA exon 18-mutant GIST in first-line setting, respectively. Despite multi-line TKIs exerted ability of disease control, drug resistance remained an obstacle for preventing rapid disease progression. Experimental TKIs or novel therapeutic targets may further improve treatment efficacy. Immune checkpoint inhibitors such as anti-programmed cell death protein-1 (PD1) and anti-CTL-associated antigen 4 (CTLA-4) showed moderate response in early phase trials composed of heavily pretreated patients. KIT/PDGFRα wild-type GISTs are generally less sensitive to imatinib and late-line TKIs. Recent studies demonstrated that targeting fibroblast growth factor receptor signaling may be a potential target for the wild-type GISTs.

Epidermal growth factor receptor tyrosine kinase inhibitors for de novo T790M mutation: A retrospective study of 44 patients.

BACKGROUND: This study aimed to evaluate possible treatment strategies for patients with de novo T790M mutation-positive (T790M+) non-small-cell lung cancer (NSCLC). METHODS: Patients diagnosed with de novo T790M+ NSCLC and treated with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) between 2011 and 2018 at a regional hospital in Taiwan were retrospectively reviewed. Their clinicopathological characteristics and subsequent treatment information were collected, and potential prognostic factors were identified using univariate and multivariate analyses. RESULTS: All tumors with T790M mutations coexisted with sensitizing mutations. Through the last follow-up in May 2021, afatinib and osimertinib demonstrated better progression-free survival (PFS, p < 0.01) and overall survival (OS, p < 0.01) than gefitinib and erlotinib. Additionally, patients with low T790M ratios had better PFS than those with high T790M ratios, implying that the proportion of T790M+ tumors determined the response to EGFR-TKIs. Multivariate analysis confirmed that both EGFR-TKI treatment (osimertinib hazard ratio [HR] 0.06, 95% confidence interval [CI] 0.01-0.30; afatinib HR 0.09, 95% CI 0.02-0.39) and a low T790M ratio (HR 0.29, 95% CI 0.12-0.69) were independently favorable prognostic factors for patients with de novo T790M+ NSCLC. Median PFS was 6.1 (95% CI 4.4-7.8) months. In addition, patients treated with first-generation (1G)/second-generation (2G) EGFR-TKIs followed by osimertinib (n = 8) demonstrated the best OS compared with patients treated with frontline osimertinib (n = 5) or 1G/2G EGFR-TKIs without osimertinib (n = 28, p < 0.01). CONCLUSION: Sequential TKIs may represent an alternative option for de novo T790M mutation, particularly frontline afatinib and tumors with low T790M ratios.

Real-world Afatinib Outcomes in Advanced Non-small Cell Lung Cancer Harboring EGFR Mutations.

BACKGROUND/AIM: Afatinib is a standard treatment for patients with advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. Osimertinib can overcome the treatment resistance-associated EGFR T790M mutation, and the sequence of afatinib followed by osimertinib is an effective therapeutic strategy for NSCLC patients. This study comprehensively evaluated the outcomes of sequential therapy following frontline afatinib and identified predictive factors for T790M mutation acquisition. PATIENTS AND METHODS: Data from patients with advanced NSCLC treated with frontline afatinib at a Taiwanese hospital group from June 2014 to March 2018 were retrospectively reviewed. The EGFR T790M mutation was detected by tissue sequencing or liquid biopsy. The patients' clinicopathological features were collected, and univariate and multivariate analyses were performed to identify potential predictive and prognostic factors. RESULTS: A total of 635 patients treated with afatinib were enrolled in this study. Until August 2021, 553 patients experienced progression, and 225 patients underwent T790M mutation testing. The T790M positive rate was 54.2%. Both exon 19 deletion and progression-free survival were associated with T790M positivity. Osimertinib was found to be effective in T790M-positive but not T790M-negative NSCLC. The median overall survival (OS) was 61.8 months for patients with T790M mutation undergoing later-line osimertinib compared with 30.1 months for patients without T790M mutation undergoing chemotherapy only. Osimertinib independently prolonged OS after afatinib progression. CONCLUSION: This study confirmed the efficacy of sequential afatinib and osimertinib treatment. T790M mutation detection and osimertinib availability are important for prolonging survival in patients with NSCLC harboring EGFR mutations.

Risk Stratification Using a Novel Nomogram for 2190 EGFR-Mutant NSCLC Patients Receiving the First or Second Generation EGFR-TKI.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the standard treatment for EGFR mutation-positive (EGFRm+) non-small cell lung cancer (NSCLC). This study aimed to create a novel nomogram to help physicians suggest the optimal treatment for patients with EGFRm+ NSCLC. Records of 2190 patients with EGFRm+ NSCLC cancer who were treated with EGFR-TKIs (including gefitinib, erlotinib, and afatinib) at the branches of a hospital group between 2011 and 2018 were retrospectively reviewed. Their clinicopathological characteristics, clinical tumor response, progression-free survival (PFS), and overall survival (OS) data were collected. Univariate and multivariate analyses were performed to identify potential prognostic factors to create a nomogram for risk stratification. Univariate analysis identified 14 prognostic factors, and multivariate analysis confirmed the pretreatment independent factors, including Eastern Cooperative Oncology Group performance status, morphology, mutation, stage, EGFR-TKIs (gefitinib, erlotinib, or afatinib), and metastasis to liver, brain, bone, pleura, adrenal gland, and distant lymph nodes. Based on these factors, a novel nomogram was created and used to stratify the patients into five different risk groups for PFS and OS using recursive partitioning analysis. This risk stratification can provide additional information to clinicians and patients when determining the optimal therapeutic options for EGFRm+ NSCLC.

Comparison of Different Tyrosine Kinase Inhibitors for Treatment of Poor Performance Status Patients with EGFR-Mutated Lung Adenocarcinoma.

The aim of this retrospective study was to investigate the tolerability and survival outcomes of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) treatment in patients with a performance status ≥ 2. The data for 517 patients treated with EGFR-TKIs between January 2011 and January 2018 at a regional hospital in northern Taiwan were analyzed. Clinical and pathological features were collected, and univariate as well as multivariable analyses were undertaken to identify potential prognostic factors. The overall objective response rate, median progression-free survival (PFS), and median overall survival (OS) were 56.3%, 11.4 months, and 15.3 months, respectively. The mutation status (exon 19 deletion), locally advanced disease, dose adjustment, and the lack of liver and pleural metastasis were independent and favorable prognostic factors for PFS. Age < 60 years, mutation status (exon 19 deletion), dose adjustment, and lack of lung, liver, and no pleural metastasis were independent and favorable prognostic factors for OS. GFR-TKIs demonstrated acceptable efficacy and safety in the current cohort. Dose adjustment was identified as an independent prognostic factor for both PFS and OS, regardless of which EGFR-TKIs were used. The current research provided novel evidence of the clinical prescription of frontline EGFR-TKIs for EGFR-mutated lung adenocarcinoma patients with a PS score ≥2.

Feasibility and effectiveness of afatinib for poor performance status patients with EGFR-mutation-positive non-small-cell lung cancer: a retrospective cohort study.

BACKGROUND: Afatinib is one of the standard treatments for patients with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC). However, data on the use of afatinib in patients with poor performance status (PS ≥ 2) are limited. This study aimed to retrospectively review the clinical outcomes and safety of afatinib treatment in EGFR-mutation-positive (EGFRm+) NSCLC patients with PS ≥ 2. METHODS: The data for 62 patients who were treated at Linkou Chang Gung Memorial Hospital from January 2010 to August 2019 were retrospectively reviewed. Patients' clinicopathological features were obtained, and univariate and multivariate analyses were performed to identify possible prognostic factors. Data on adverse events were collected to evaluate general tolerance for afatinib therapy. RESULTS: Until February 2020, the objective response rate, disease control rate, median progression-free survival (PFS), and overall survival (OS) were 58.1% (36/62), 69.4% (43/62), 8.8 months, and 12.9 months, respectively. The absence of liver metastasis (PFS: p = 0.044; OS: p = 0.061) and good disease control (p < 0.001 for PFS and OS) were independent favorable prognostic factors for PFS and OS. Bone metastasis (p = 0.036) and dose modification (reduction/interruption, p = 0.021) were predictors of disease control. CONCLUSION: Afatinib demonstrated acceptable efficacy and safety in the current cohort. This study provided evidence to support the use of afatinib as a first-line treatment in EGFRm+ NSCLC patients with poor PS.

PD-L1 Immunohistochemistry Comparability and Their Correlation with Clinical Characteristics in NSCLC.

BACKGROUND: PD-L1 expression is an important predictive factor of response to therapy with immune checkpoint inhibitors (ICIs). This study was designed to retrospectively analyze the concordance of PD-L1 measurements using three different assays (Dako22C3, Dako28-8, and SP142) in NSCLC patients and to find possible predictors of high PD-L1 expression. MATERIALS AND METHODS: Data of 144 patients with histologically confirmed NSCLC and available PD-L1 measurements treated at the Taoyuan General Hospital from 2018 to 2019 were retrospectively reviewed in the study. Patients' characteristics, including age, sex, clinical stage (T, N, and M) of NSCLC (AJCC, 8th edition), and EGFR/ALK alterations, were analyzed for association with PD-L1 expression. RESULTS: Measurements of PD-L1 expression levels with Dako22C3 and Dako28-8 were comparable while SP142 showed lower levels of PD-L1 expression. The overall agreement between Dako22C3 and Dako28-8 was 82.2% and 91.6% for both 1% and 50% TPS cut-offs, respectively. The above findings were confirmed by Cohen's kappa. In addition, we found that PD-L1 expression was significantly associated with advanced N stage but not with T and M stages. CONCLUSION: Dako22C3 and Dako28-8 showed comparable results in assessing PD-L1 levels. Future prospective studies are needed to validate these findings. N stage may be a good predictor for PD-L1 expression.

The association between immune-related adverse events and survival outcomes in Asian patients with advanced melanoma receiving anti-PD-1 antibodies.

BACKGROUND: The association between immune-related adverse events (irAEs) and survival outcomes in patients with advanced melanoma receiving therapy with immune checkpoint inhibitors (ICIs) has not been well established, particularly in Asian melanoma. METHODS: We retrospectively reviewed 49 melanoma patients undergoing therapy with ICIs (anti-PD-1 monotherapy), and analyzed the correlation between irAEs and clinical outcomes including progression-free survival (PFS) and overall survival (OS). RESULTS: Overall, the patients who experienced grade 1-2 irAEs had longer PFS (median PFS, 4.6 vs. 2.5 months; HR, 0.52; 95% CI: 0.27-0.98; p = 0.042) and OS (median OS, 15.2 vs. 5.7 months; HR, 0.50; 95% CI: 0.24-1.02; p = 0.058) than the patients who did not experience irAEs. Regarding the type of irAE, the patients with either skin/vitiligo or endocrine irAEs showed better PFS (median PFS, 6.1 vs. 2.7 months; HR, 0.40, 95% CI: 0.21-0.74; p = 0.003) and OS (median OS, 18.7 vs. 4.5 months; HR, 0.34, 95% CI: 0.17-0.69, p = 0.003) than patients without any of these irAEs. CONCLUSIONS: Melanoma patients undergoing anti-PD-1 monotherapy and experiencing mild-to-moderate irAEs (grade 1-2), particularly skin (vitiligo)/endocrine irAEs had favorable survival outcomes. Therefore, the association between irAEs and the clinical outcomes in melanoma patients undergoing anti-PD-1 ICIs may be severity and type dependent.

Prognostic Value of Lymph Node-To-Primary Tumor Standardized Uptake Value Ratio in Esophageal Squamous Cell Carcinoma Treated with Definitive Chemoradiotherapy.

We aimed to investigate the prognostic value of the relative maximum standardized uptake value (SUV) of metastatic lymph node (LN) compared with that of primary tumor (SUVLN / SUVTumor) based on a pretreatment [18F]-FDG PET/CT scan in patients with clinically node-positive esophageal squamous cell carcinoma (cN+ ESCC) treated with definitive chemoradiotherapy (dCRT). We retrospectively evaluated cN+ ESCC patients who underwent a PET/CT scan before dCRT. Time-dependent receiver operating characteristics analysis was performed to identify the optimal cutoff value for SUVLN / SUVTumor. Prognostic influences of SUVLN / SUVTumor on distant metastasis-free survival (DMFS) and overall survival (OS) were evaluated using the Kaplan-Meier method and log-rank test for univariate analysis and Cox's proportional hazards regression model for multivariate analysis. We identified 112 patients with newly diagnosed cN+ ESCC. After a median follow-up of 32.0 months, 50 (44.6%) patients had distant failure and 84 (75.0%) patients died. Patients with high SUVLN / SUVTumor (≥ 0.39) experienced worse outcomes than low SUVLN / SUVTumor (< 0.39) (two-year DMFS: 26% vs. 70%, p < 0.001; two-year OS: 21% vs. 48%, p = 0.001). Multivariate analysis showed that SUVLN / SUVTumor was an independent prognostic factor for both DMFS (adjusted HR 2.24, 95% CI 1.34-3.75, p = 0.002) and OS (adjusted HR 1.61, 95% CI 1.03-2.53, p = 0.037). Pretreatment of SUVLN / SUVTumor is a simple and useful marker for prognosticating DMFS and OS in cN+ ESCC patients treated with dCRT, which may help in tailoring treatment and designing future clinical trials.

Validation and application of a prognostic model for patients with advanced pancreatic cancer receiving palliative chemotherapy.

BACKGROUND: We previously developed a robust prognostic model (GS model) to predict the survival outcome of patients with advanced pancreatic cancer (APC) receiving palliative chemotherapy with gemcitabine plus S-1 (GS). This study aimed to validate the application of the GS model in APC patients receiving chemotherapy other than the GS regimen. PATIENTS AND METHODS: We retrospectively analyzed 727 APC patients who received first-line palliative chemotherapy other than the GS regimen between 2010 and 2016 at four institutions in Taiwan. The patients were categorized into three prognostic groups based on the GS model for comparisons of survival outcome, best tumor response, and in-group survival differences with monotherapy or combination therapy. RESULTS: The median survival times for the good, intermediate, and poor prognostic groups were 13.4, 8.4, and 4.6 months, respectively. The hazard ratios for the comparisons of intermediate and poor to good prognostic groups were 1.51 (95% confidence interval [CI]), 1.22-1.88, P < .001) and 2.84 (95% CI, 2.34-3.45, P < .001). The best tumor responses with either partial response or stable disease were 57.5%, 40.4%, and 17.2% of patients in the good, intermediate, and poor prognostic groups (P < .001), respectively. For patients in the good prognostic group, first-line chemotherapy with monotherapy and combination therapy had similar median survival times (13.8 vs 12.9 months, P = .26), while combination therapy showed a better median survival time than monotherapy in patients in the intermediate and poor prognostic groups (8.5 vs 8.0 months, P = .038 and 5.7 vs 3.7 months, P = .001, respectively). CONCLUSION: The results of our study supported the application of the GS model as a general prognostic tool for patients with pancreatic cancer receiving first-line palliative chemotherapy with gemcitabine-based regimens.